DESCRIPTION The overall goal of the proposed research is to understand the cellular mechanisms that underlie the processing of information by single neurons. A key step in this processing is the conversion of membrane potential into action potentials. Recent work in pyramidal neurons suggests that, due to a low threshold, initiation of action potentials occurs in the axon. What determines this threshold, however, is not understood. The first hypothesis to be tested is that the threshold for action potential initiation is lower in the axon than in the soma because the density of Na+ channels is high and the density of A-type channels is low in the axon. The Specific Aims are 1) To determine and compare the relative densities and biophysical parameters of Na+ and K+ channels in the axon and soma using patch-clamp techniques and 2) to determine which channels are major determinants of threshold in the axon by manipulating threshold pharmacologically during whole-cell recording. The second hypothesis is that inhibitory synapses on the initial segment increase action potential threshold by decreasing current flow to the site of initiation in the axon. The Specific Aims are to 3) determine the voltage drop between the soma and axon and to measure thresholds with and without activation of GABAA receptors on the initial segment, and 4) to determine if the site of action potential initiation shifts to the dendrites when the threshold is raised by activation of GABAA receptors on the initial segment and soma. These studies will provide much needed data on the cellular mechanisms underlying action potential initiation and its modulation.